Schizophrenia-risk and urban birth are associated with proteomic changes in neonatal dried blood spots

Abstract

In the present study, we tested whether there were proteomic differences in blood between schizophrenia patients after the initial onset of the disorder and controls; and whether those differences were also present at birth among neonates who later developed schizophrenia compared to those without a psychiatric admission. We used multiple reaction monitoring mass spectrometry to quantify 77 proteins (147 peptides) in serum samples from 60 first-onset drug-naive schizophrenia patients and 77 controls, and 96 proteins (152 peptides) in 892 newborn blood-spot (NBS) samples collected between 1975 and 1985. Both serum and NBS studies showed significant alterations in protein levels. Serum results revealed that Haptoglobin and Plasma protease C1 inhibitor were significantly upregulated in first-onset schizophrenia patients (corrected P < 0.05). Alpha-2-antiplasmin, Complement C4-A and Antithrombin-III were increased in first-onset schizophrenia patients (uncorrected P-values 0.041, 0.036 and 0.013, respectively) and also increased in newborn babies who later develop schizophrenia (P-values 0.0058, 0.013 and 0.044, respectively). We also tested whether protein abundance at birth was associated with exposure to an urban environment during pregnancy and found highly significant proteomic differences at birth between urban and rural environments. The prediction model for urbanicity had excellent predictive performance in both discovery (area under the receiver operating characteristic curve (AUC) = 0.90) and validation (AUC = 0.89) sample sets. We hope that future biomarker studies based on stored NBS samples will identify prognostic disease indicators and targets for preventive measures for neurodevelopmental conditions, particularly those with onset during early childhood, such as autism spectrum disorder.

Multimodel inference for biomarker development: an application to schizophrenia

“…The Cologne study (referred to as the ‘training set’), as previously described 13 , consisted of serum samples from 60 first-onset drug-naive schizophrenia patients and 79 age and sex matched controls recruited by the Department of Psychiatry, University of Cologne (Supplementary Table 1). The Rotterdam study (referred to as the ‘independent test set’), as previously described 14 , consisted of nine first-onset drug-naive male schizophrenia patients and 12 male controls recruited by the Erasmus Medical Centre in Rotterdam (Supplementary Table 1).…”

“…In the present study, rather than making predictions based on a single-best model selected from a data set, we adopted a multimodel approach to make predictions for the probability of having schizophrenia based on a set of models to allow for any uncertainty in model selection. The schizophrenia data analysed consisted of two-independent mass spectrometry (MS) multiple reaction monitoring (MRM) proteomic data sets (147 peptides from 77 proteins) of first-onset drug-naive schizophrenia patients and controls 13,14 that were used in the present study as training and test sets. The sensitivity of model selection to small changes in the training data was evaluated by model selection using least absolute shrinkage and selection operator (lasso) regression with the resampling approach of repeated tenfold cross-validation 15 .…”

Integrated Lipidomics and Proteomics Point to Early Blood-Based Changes in Childhood Preceding Later Development of Psychotic Experiences: Evidence From the Avon Longitudinal Study of Parents and Children

“…Therefore, increased PLG such as we described in PEs is very consistent with higher specific PC and LPC concentrations in the PEs group. Our findings of elevated levels of PLG in subjects who later report PEs are intriguing in light of recent evidence that blood-derived PLG drives brain inflammation (78) and evidence that alpha2-antiplasmin, which is the main inhibitor of PLG-derived plasmin, is upregulated in schizophrenia (79) . Interestingly, proteomics studies discovered a high number of complement and coagulation proteins as lipoprotein-associated components, such as complement 4A, complement C4B, vitronectin, clusterin, complement factor H, alpha1/2-antiplasmin, and kininogen, among others (80) .…”

The bradykinin system in stress and anxiety in humans and mice

“…In bipolar disorder, the expression of KNG1 mRNA is upregulated in the orbitofrontal cortex 33 . Elevated plasma KNG1 protein levels can be detected even before the onset of disease, in neonates who later develop schizophrenia 34 and in children who later develop psychotic disorder 35 . We have observed in a first episode psychosis study that antipsychotic drug treatment influences BDKRB1 gene expression levels in blood leukocytes 36 .…”